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A response from the author of the article "Acute Cholangitis: Understanding Predictors of Outcome," is presented.

Background Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patientreported outcomes is undetermined. Aim To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo. Methods We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial. Results Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 ± 0.17 vs. 6.40 ± 0.17, P = 0.001, and 10.61 ± 0.07 vs. 11.00 ± 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 ± 0.35 vs. 7.10 ± 0.37, P = 0.020 for pain intensity; 10.36 ± 0.12 vs. 10.93 ± 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up. Conclusions In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline. [ABSTRACT FROM AUTHOR]

Background Predictors of organ failure and the impact of early endoscopic retrograde cholangiopancreatography ( ERCP) on outcomes in patients with acute cholangitis are unclear. Aim To identify factors associated with persistent organ failure and assess the impact of early ERCP on outcomes in hospitalised patients with cholangitis. Methods Consecutive hospitalised patients who received ERCP at two centres for cholangitis from 4/2005-3/2013 were retrospectively reviewed. Delayed ERCP was defined as ERCP ≥48 h after hospitalisation. Primary outcome was persistent organ failure at >48 h after hospitalisation (≥1.5 times rise in creatinine levels from baseline values to ≥1.5 mg/dL or need for dialysis, mechanical ventilation and/or hypotension requiring vasopressor). Results 203 patients (mean age 59 ± 19 years) had ERCP for cholangitis: 115 with choledocholithiasis, 48 with other benign obstructions and 40 with malignant strictures. Forty-five (22%) patients had persistent organ failure at >48 h and 11 (5%) died. On multivariate analysis, Charlson Comorbidity Index >2 ( OR = 4.6, 95% CI = 1.5-13.8), systemic inflammatory response syndrome ( SIRS; OR = 3.2, 95% CI = 1.1-9.8), hypoalbuminemia ( OR = 3.3, 95% CI = 1.4-7.9), bacteremia ( OR = 2.8, 95% CI 1.3-6.2) and delayed ERCP( OR = 3.1, 95% CI: 1.4-7.0) were associated with persistent organ failure. Every 1-day delay in ERCP was associated with a 17% (95% CI = 5-29%) relative risk increase in persistent organ failure after adjusting for significant factors. Conclusions Delay in ERCP beyond 48 h was associated with persistent organ failure in hospitalised patients with acute cholangitis. Other factors included increased comorbidities, SIRS, hypoalbuminemia and bacteremia. Early ERCP performed within 48 h after presentation in patients with cholangitis may improve outcomes. [ABSTRACT FROM AUTHOR]

Background Although gastroenterologists are asked to perform colonoscopy in patients with metastatic cancer of unknown primary ( MCUP), studies evaluating this practice are lacking. Aim To determine the yield and cost of colonoscopy in patients referred for colonoscopy with an indication of MCUP. Methods We prospectively and retrospectively assessed colonoscopies performed from 2000 to 2011 at a county, a university, and a Veterans Administration medical centre to identify patients referred for colonoscopy for the indication of MCUP. Exclusion criteria included overt or occult bleeding, iron-deficiency anaemia, familial-colon-cancer syndrome, prior colon cancer, imaging suggesting colorectal lesion, and palpable rectal mass. Outcomes were the number of primary colon cancers and costs based on 2012 Medicare reimbursements. Results Two (1%) of the 160 patients meeting enrollment criteria had a primary colon cancer identified, and both died within 1 month after diagnosis without receiving therapy targeted at colon cancer. One patient without colon cancer had a perforation because of colonoscopy, which required surgery and colostomy. The cost of a strategy of routinely performing colonoscopy in patients referred with MCUP was $84 736 per colon primary identified. Conclusions Primary colon cancer was rarely identified at colonoscopy in patients with MCUP and no standard indications for diagnostic colonoscopy. Furthermore, the cost to diagnose one additional colon primary was very high. Those with colon cancer had advanced disease and were unable to benefit from targeted therapy. Routine colonoscopy for MCUP cannot be recommended at present. [ABSTRACT FROM AUTHOR]

Background Scant information is available regarding patients with upper gastrointestinal bleeding ( UGIB) from tumours. Aim To determine the presentation, endoscopic findings, treatment and outcomes in patients with UGIB from malignant tumours and identify risk factors associated with rebleeding. Methods Consecutive patients who were hospitalised with haematemesis, melena or haematochezia and underwent upper endoscopy were identified retrospectively by reviewing an endoscopy database. Patients with UGIB due to biopsy-proven malignant tumours were studied. Results Tumours were the source of bleeding in 106 (5%) of 2,166 patients with UGIB. Tumours were oesophageal in 17 (16%), gastric in 77 (73%) and duodenal in 12 (11%). At presentation, 84 (79%) did not have known cancer previously, and 79 (75%) had metastatic disease. Seventy-seven (73%) received transfusions at index hospitalisation. At endoscopy, 32 (30%) had active bleeding (31 oozing, 1 spurting). Among actively bleeding patients, haemostasis was achieved in 12 (86%) of 14 receiving endoscopic therapy and all 18 not receiving endoscopic treatment. Hospitalisation for rebleeding occurred in 50 (49%) of 103 at a median of 30 days (3-885). On multivariate analysis, age ≤60 years (OR = 2.49, 95% CI 1.06-5.81) and haemodynamic instability (OR = 2.42, 95% CI 1.08-5.46) were associated with rebleeding. Conclusions Patients presenting with tumour-associated UGIB have substantial blood loss, with three-quarters requiring transfusion at presentation. Initial haemostasis occurs in almost all patients, with or without endoscopic therapy, but rebleeding requiring repeat hospitalisation occurs in approximately half the patients and is more common in patients who are ≤60 years of age and have haemodynamic instability at presentation. [ABSTRACT FROM AUTHOR]

Background: Mass spectrometry and proteomic analyses have become powerful tools for the analysis of proteins and peptides. Investigation of proteins contained in the various layers of the avian eggshell has focused entirely on domesticated species. It has been widely assumed that this existing research can inform the study of wild bird species despite the fact that the vast majority of the diversity in avian species (~95%) exists outside the Orders to which domestic and poultry species belong. Museum collections offer a potentially valuable source of material for studying composition of wild avian eggshell matrix proteins. We used museum and fresh eggshells of common quails Coturnix coturnix to compare the protein composition of their organic matrices. Four eggs of domestic chickens were analysed simultaneously as a control for comparison to the fresh and museum quail eggs. The determination of the proteins was carried out using enzymatic cleavage followed by high-performance mass spectrometry. Results: We found that some of the expected key eggshell proteins (3 out of 11) were not present in the samples of museum quail egg. These proteins were either entirely absent from the museum eggs or the technique was unable to detect them. There was no pattern in the absent proteins in the sense of protein function or where they are located within the eggshell. Conclusion: We conclude it is likely that such studies on museum specimens using a proteomic approach will be limited in coverage of proteins and may, therefore, be misleading. [ABSTRACT FROM AUTHOR]

Background Although ‘best practice’ guidelines for dyspepsia management have been disseminated, it remains unclear whether providers adhere to these guidelines. Aim To compare adherence to ‘best practice’ guidelines among dyspepsia experts, community gastroenterologists and primary-care providers (PCPs). Methods We administered a vignette survey to elicit knowledge and beliefs about dyspepsia including a set of 16 best practices, to three groups: (i) dyspepsia experts; (ii) community gastroenterologists and (iii) PCPs. Results The expert, community gastroenterologist and PCP groups endorsed 75%, 73% and 57% of best practices respectively. Gastroenterologists were more likely to adhere with guidelines than PCPs ( P < 0.0001). PCPs were more likely to define dyspepsia incorrectly, overuse radiographic testing, delay endoscopy, treat empirically for Helciobacter pylori without confirmatory testing and avoid first-line proton pump inhibitors (PPIs). PCPs had more concerns about adverse events with PPIs [e.g. osteoporosis ( P = 0.04), community-acquired pneumonia ( P = 0.01)] and higher level of concern predicted lower guideline adherence ( P = 0.04). Conclusions Gastroenterologists are more likely than PCPs to comply with best practices in dyspepsia, although compliance remains incomplete in both groups. PCPs harbour more concerns regarding long-term PPI use and these concerns may affect therapeutic decision making. This suggests that best practices have not been uniformly adopted and persistent guideline-practice disconnects should be addressed. [ABSTRACT FROM AUTHOR]

Background When faced with the same facts, physicians often make different decisions. Aim To perform a survey to measure the process of care and variations in decision-making in nonvariceal upper gastrointestinal tract haemorrhage (NVUGIH) and compare results between experts and non-experts. Methods We administered a vignette survey to elicit knowledge and beliefs about NVUGIH, including 13 ‘best practice’ guidelines. We compared guideline compliance between experts and non-experts. Results One hundred and eighty-eight gastroenterologists responded (46%). Experts endorsed more ‘best practices’ than non-experts (93% vs . 85%; P = 0.002). Non-experts were more likely to endorse incorrectly bolus dosing vs . continuous infusion of intravenous proton pump inhibitors (PPIs; 92% vs . 64%; P = 0.005) and to select standard-channel vs . large-channel endoscopes in high-risk bleeding (100% vs . 85%; P = 0.04). There were wide variations within groups regarding the timing of nasogastric lavage, use of promotility agents, use of hemoclips and appropriateness of snaring clots overlying ulcers. Conclusions Experts are more likely to comply with NVUGIH guidelines. Non-experts diverge from experts in the dosing of PPIs and choice of endoscope in high-risk bleeding. Moreover, there are wide variations in key practices even within groups. This suggests that best practices have been generally well disseminated, but that persistent disconnects exist that should be further investigated. [ABSTRACT FROM AUTHOR]

Background Treatment with a continuous i.v. proton pump inhibitor is presumed to promote clot formation and stability by sustaining intragastric pH ≥ 6. Aim We postulated that very frequent oral dosing of proton pump inhibitors should simulate i.v. infusion and achieve similar pH control. Methods Twenty healthy volunteers were stratified by Helicobacter pylori status (10 positive; 10 negative) and had determination of CYP2C19 status. After an overnight fast, an intragastric pH probe was placed. Subjects received 120 mg of lansoprazole at 8am and 30 mg every 3 h until 8pm. Intragastric pH was measured over 24 h, and lansoprazole plasma concentrations were determined at five time points. Results Intragastric pH was ≥6 for 41% (95% CI: 30–53%) of the 15-h period from 8am–11pm and 46% (95% CI: 35–56%) of the 24-h period (8–8am). The mean proportion of patients with pH ≥6 was not significantly different in H. pylori-positive vs. negative patients. Only 25% of subjects sustained pH ≥6 for at least 60% of the 15-h period, and 35% had a sustained pH ≥6 for at least 60% of the 24-h period. Conclusions A dose of 120 mg of oral lansoprazole followed by standard 30 mg doses of lansoprazole every 3 h did not reliably sustain pH at the desired level of 6. [ABSTRACT FROM AUTHOR]

: To rationalize decision making around the use of different non-steroidal anti-inflammatory drug (NSAID) treatment strategies in patients with varying degrees of gastrointestinal and cardiovascular risk. : The panel comprised nine physicians (three rheumatologists, two internists, two gastroenterologists and two cardiologists) from geographically diverse areas practising in community-based settings ( n = 4) and academic institutions ( n = 5). A literature review was performed by the authors on the risks, benefits and costs of NSAIDs, cyclo-oxygenase-2-specific inhibitors and proton pump inhibitor co-therapy. The RAND/UCLA Appropriateness Method was used to rate 304 clinical scenarios as ‘appropriate’, ‘uncertain’ or ‘inappropriate’. : In patients with no previous gastrointestinal event and not concurrently on aspirin (low risk), the panel rated the use of an NSAID alone as ‘appropriate’ for those aged < 65 years, and the use of an NSAID +proton pump inhibitor or cyclo-oxygenase-2-specific inhibitor + proton pump inhibitor as ‘inappropriate’. For patients aged > 65 years and at low risk, an NSAID or cyclo-oxygenase-2-specific inhibitor alone was rated as ‘uncertain’. For patients with a previous gastrointestinal event or who concurrently received aspirin, an NSAID alone was rated as ‘inappropriate’, and either a cyclo-oxygenase-2-specific inhibitor or an NSAID +proton pump inhibitor was rated as ‘appropriate’. Finally, for patients with a previous gastrointestinal event and on aspirin, an NSAID or cyclo-oxygenase-2-specific inhibitor in conjunction with a proton pump inhibitor was rated as ‘appropriate’. : Clinicians and managed care entities need to balance the risks, benefits and costs of NSAIDs, cyclo-oxygenase-2-specific inhibitors and the prophylactic use of proton pump inhibitors. The guidelines given here can assist this process. [ABSTRACT FROM AUTHOR]

To help guide treatment decisions and clinical trial matching, tumor genomic profiling is an essential precision oncology tool. Liquid biopsy, a complementary approach to tissue testing, can assess tumor-specific DNA alterations circulating in the blood. Labcorp Plasma Complete is a next-generation sequencing, cell-free DNA comprehensive genomic profiling test that identifies clinically relevant somatic variants across 521 genes in advanced and metastatic solid cancers. Over 800 unique sequencing libraries across 27 cancer types were evaluated to establish analytical sensitivity, specificity, accuracy, and precision, reproducibility, and repeatability. Sensitivity was verified for each variant type, with a median variant allele frequency (VAF) of 1.25% and 1.27% for panel-wide single-nucleotide variants and insertions/deletions (sequence variants), respectively, with <1% VAF sensitivity observed for clinically actionable variants, 1.72-fold for copy number amplifications, 0.48% fusion read fraction for translocations, and 0.47% sequence mutation VAF for microsatellite instability-high. Analytical specificity was 99.9999% for single-nucleotide variants and 100% for all other variant types. Precision, reproducibility, and repeatability resulted in 94.9% average positive agreement and 99.9% average negative agreement for sequence variants and 100% average positive agreement and average negative agreement for copy number amplifications, translocations, and microsatellite instability. Orthogonal assays were used to assess accuracy, demonstrating an aggregate analytical concordance of 97.4% positive percentage agreement and >99.99997% negative percentage agreement for all variants. Overall, the test demonstrates high sensitivity, specificity, accuracy, and robustness to enable informed clinical decision-making., Competing Interests: Disclosure Statement All authors are employed by Labcorp and/or Labcorp Oncology. E.L.V., J.B.J., C.M., K.C.V., K.M.R.G., M.S., E.A.S., T.J.J., B.J.C., M.E., S.H.R., and A.E.G. are Labcorp shareholders/stock owners., (Copyright © 2025. Published by Elsevier Inc.)

FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Tregs). While mice exclusively express FOXP3 in Tregs, humans also transiently express FOXP3 in stimulated conventional CD4+ T cells (Tconvs). Mechanisms governing these distinct expression patterns remain unknown. Here, we performed CRISPR screens tiling the FOXP3 locus and targeting TFs in human Tregs and Tconvs to discover cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv FOXP3 expression depended on a subset of Treg CREs and Tconv-selective positive (TcNS+) and negative (TcNS-) CREs. The CREs are occupied and regulated by TFs we identified as critical regulators of FOXP3. Finally, mutagenesis of murine TcNS- revealed that it is critical for restriction of FOXP3 expression to Tregs. We discover CRE and TF circuitry controlling FOXP3 expression and reveal evolution of mechanisms regulating a gene indispensable to immune homeostasis., Highlights: Comprehensive CRISPR maps of CREs and TFs controlling FOXP3 in human Tregs and TconvsKey TFs that control FOXP3 directly occupy and regulate CREs forming TF-CRE circuitsA previously unknown negative CRE stringently restricts FOXP3 to Tregs in mice.

In 2019, the U.S. Department of Agriculture's (USDA) Food Safety and Inspection Service (FSIS) provided revised guidance for labeling claims of "raised without antibiotics" (RWA) and similar terms for meat and poultry produced in the US. In 2022, Price et al. published a study reporting that 15% of RWA-labeled cattle contained antibiotic residues in urine samples. In 2023, the USDA embarked on the project reported herein to independently determine the extent of antibiotic drug residues present in kidney and liver tissues from slaughtered cattle purported to be RWA. In this study, FSIS inspectors randomly collected kidney and liver tissues from 189 RWA animals in 79 slaughter establishments across the US. The samples were monitored for 185 veterinary drugs multiple times by different means, including liquid-chromatography coupled with tandem mass spectrometry (LC-MS/MS) and quadrupole high-resolution MS with an orbital ion trap instrument (LC-Q/orbitrap). Samples from 37 animals (20%) met the analytical identification criteria for at least one antibiotic confirmed in at least two analyses. Multiple antibiotics were determined in 11 RWA animals. Macrolides (tulathromycin, tildipirosin, tilmicosin, and gamithromycin) were confirmed in 20 (11%) of the RWA animals. The ionophore, monensin, was also confirmed in tissues from 11 samples, with unconfirmed/partial identifications in 8 others. Tetracyclines were confirmed in samples from 12 animals, several of which were found to contain multiple antibiotic residues. One animal each was also found to be positive for sulfamethazine (a sulfonamide antibiotic) and metabolites of penicillin G (a β-lactam antibiotic). Although they are not antibiotics, two anthelmintics (fenbendazole and eprinomectin) were confirmed in tissues from 3 RWA animals. FSIS has informed the slaughter establishments with positive results and advised them to conduct a root cause analysis and implement corrective actions.

Aim: The Test of Gross Motor Development Third Edition (TGMD-3) is used to assess the development of fundamental movement skills in children from 3 to 10 years old. This study aimed to evaluate the intra-rater, inter-rater, and test-retest reliability and to determine the minimal detectable change (MDC) value of the TGMD-3 in children with developmental coordination disorder (DCD)., Methods: The TGMD-3 was administered to 20 children with DCD. The child's fundamental movement skills were recorded using a digital video camera. Reliability was assessed at two occasions by three raters using the generalizability theory., Results: The TGMD-3 demonstrates good inter-rater reliability for the locomotor skills subscale, the ball skills subscale, and the total score (φ = 0.77 - 0.91), while the intra-rater reliability was even higher (φ = 0.94 - 0.97). Test-retest reliability was also shown to be good (φ = 0.79-0.93). The MDC 95 was determined to be 10 points., Conclusion: This study provides evidence that the TGMD-3 is a reliable test when used to evaluate fundamental movement skills in children with DCD and suggests that an increase of 10 points represents a significant change in the motor function of a child with DCD.

Background & Aims: Early identification and accurate characterization of overt gastrointestinal bleeding (GIB) enables opportunities to optimize patient management and ensures appropriately risk-adjusted coding for claims-based quality measures and reimbursement. Recent advancements in generative artificial intelligence, particularly large language models (LLMs), create opportunities to support accurate identification of clinical conditions. In this study, we present the first LLM-based pipeline for identification of overt GIB in the electronic health record (EHR). We demonstrate 2 clinically relevant applications: the automated detection of recurrent bleeding and appropriate reimbursement coding for patients with GIB., Methods: Development of the LLM-based pipeline was performed on 17,712 nursing notes from 1108 patients who were hospitalized with acute GIB and underwent endoscopy in the hospital from 2014 to 2023. The pipeline was used to train an EHR-based machine learning model for detection of recurrent bleeding on 546 patients presenting to 2 hospitals and externally validated on 562 patients presenting to 4 different hospitals. The pipeline was used to develop an algorithm for appropriate reimbursement coding on 7956 patients who underwent endoscopy in the hospital from 2019 to 2023., Results: The LLM-based pipeline accurately detected melena (positive predictive value, 0.972; sensitivity, 0.900), hematochezia (positive predictive value, 0.900; sensitivity, 0.908), and hematemesis (positive predictive value, 0.859; sensitivity, 0.932). The EHR-based machine learning model identified recurrent bleeding with area under the curve of 0.986, sensitivity of 98.4%, and specificity of 97.5%. The reimbursement coding algorithm resulted in an average per-patient reimbursement increase of $1299 to $3247 with a total difference of $697,460 to $1,743,649., Conclusions: An LLM-based pipeline can robustly detect overt GIB in the EHR with clinically relevant applications in detection of recurrent bleeding and appropriate reimbursement coding., (Copyright © 2025 AGA Institute. Published by Elsevier Inc. All rights reserved.)

An innovative process to multifunctional vitrimer nanocomposites with a percolative MXene minor phase is reported, marking a significant advancement in creating stimuli-repairable, reinforced, sustainable, and conductive nanocomposites at diminished loadings. This achievement arises from a Voronoi-inspired biphasic morphological design via a straight-forward three-step process involving ambient-condition precipitation polymerization of micron-sized prepolymer powders, aqueous powder-coating with 2D MXene (Ti 3 C 2 T z ), and melt-pressing of MXene-coated powders into crosslinked films. Due to the formation of MXene-rich boundaries between thiourethane vitrimer domains in a pervasive low-volume fraction conductive network, a low percolation threshold (≈0.19 vol.%) and conductive polymeric nanocomposites (≈350 S m -1 ) are achieved. The embedded MXene skeleton mechanically bolsters the vitrimer at intermediate loadings, enhancing the modulus and toughness by 300% and 50%, respectively, without mechanical detriment compared to the neat vitrimer. The vitrimer's dynamic-covalent bonds and MXene's photo-thermal conversion properties enable repair in minutes through short-term thermal treatments for full macroscopic mechanical restoration or in seconds under 785 nm light for rapid localized surface repair. This versatile fabrication method to nanocoated pre-vitrimer powders and morphologically complex nanocomposites is compatible with classic composite manufacturing, and when coupled with the material's exceptional properties, holds immense potential for revolutionizing advanced composites and inspiring next-generation smart materials., (© 2024 Wiley‐VCH GmbH.)

The continuous evolution of SARS-CoV-2 has led to the emergence of several variants of concern (VOCs) that significantly affect global health. This study aims to investigate how these VOCs affect host cells at proteome level to better understand the mechanisms of disease. To achieve this, we first analyzed the (phospho)proteome changes of host cells infected with Alpha, Beta, Delta, and Omicron BA.1 and BA.5 variants over time frames extending from 1 to 36 h post infection. Our results revealed distinct temporal patterns of protein expression across the VOCs, with notable differences in the (phospho)proteome dynamics that suggest variant-specific adaptations. Specifically, we observed enhanced expression and activation of key components within crucial cellular pathways such as the RHO GTPase cycle, RNA splicing, and endoplasmic reticulum-associated degradation (ERAD)-related processes. We further utilized proximity biotinylation mass spectrometry (BioID-MS) to investigate how specific mutation of these VOCs influence viral-host protein interactions. Our comprehensive interactomics dataset uncovers distinct interaction profiles for each variant, illustrating how specific mutations can change viral protein functionality. Overall, our extensive analysis provides a detailed proteomic profile of host cells for each variant, offering valuable insights into how specific mutations may influence viral protein functionality and impact therapeutic target identification. These insights are crucial for the potential use and design of new antiviral substances, aiming to enhance the efficacy of treatments against evolving SARS-CoV-2 variants., Competing Interests: Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Approximately 30% of patients with typical gastroesophageal reflux disease (GERD) symptoms have endoscopic evidence of erosive esophagitis (EE). 1 The severity of EE is commonly graded using the Los Angeles (LA) classification system as grade A (minimal) to D (very severe), depending on the extent of endoscopically visible mucosal breaks (Supplementary Figure 1). 2 Accurate grading of EE severity is crucial in clinical trials of medical EE treatments, as EE severity strongly influences both initial rates of healing and the likelihood of recurrence during maintenance treatment. 3,4 Almost all EE treatment studies have relied exclusively on local investigators' grading of EE severity to determine study eligibility and response to treatment. Those few studies that included central adjudication did not assess the reliability of grading by local investigators. 5 Unlike typical studies of EE treatment, the phase III clinical trial of vonoprazan versus lansoprazole for the treatment of EE (NCT04124926) mandated central adjudication of endoscopic grading for study participation. 6 The aim of the present investigation was to evaluate the rate of agreement between local investigators and central adjudicators for EE grading during screening for entrance into that clinical trial., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Mutations occurring in the spike (S) protein of SARS-CoV-2 enables the virus to evade COVID-19 vaccine- and infection-induced immunity., Methods: Here we provide a comprehensive analysis of humoral and cell-mediated immunity in 111 healthcare workers who received three or four vaccine doses and were followed up to 12 and 6 months, respectively, after the last vaccine dose. Omicron breakthrough infection occurred in 71% of the vaccinees, enabling evaluation of vaccine- and vaccine/infection-induced hybrid immunity., Results: Neutralizing antibodies were the highest against the ancestral D614G and were sequentially reduced against the Omicron variants BA.2, BA.5 and XBB.1.5. S1-specific IgG and neutralizing antibody levels were significantly higher in infected than in uninfected vaccinees, and the fourth vaccine dose in combination with a breakthrough infection resulted in high neutralizing antibody levels against all variants. T cell-mediated immunity, instead, was well retained already after two vaccine doses, and was not significantly strengthened by additional booster vaccine doses or Omicron breakthrough infections., Discussion: While humoral immunity is sensitive to mutations in the S protein and thus declined rapidly, the cell-mediated immunity is durable to antigenic variation, which may explain the good efficacy of COVID-19 vaccines against a severe disease., 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 Belik, Reinholm, Kolehmainen, Heroum, Maljanen, Altan, Österlund, Laine, Ritvos, Pasternack, Naves, Iakubovskaia, Barkoff, He, Lempainen, Tähtinen, Ivaska, Jalkanen, Julkunen and Kakkola.)

The efficacy of vonoprazan-based dual and triple therapy vs. lansoprazole-based triple therapy in the treatment of H. pylori infection was largely consistent regardless of age, sex, race, ethnicity, BMI, alcohol intake, smoking status, and study drug compliance., (© 2024 The Author(s). JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

After 4 years of the COVID-19 pandemic, SARS-CoV-2 continues to circulate with epidemic waves caused by evolving new variants. Although the rapid development of vaccines and approved antiviral drugs has reduced virus transmission and mitigated the symptoms of infection, the continuous emergence of new variants and the lack of simple-use (non-hospitalized, easy timing, local delivery, direct acting, and host-targeting) treatment modalities have limited the effectiveness of COVID-19 vaccines and drugs. Therefore, novel therapeutic approaches against SARS-CoV-2 infection are still urgently needed. As a positive-sense single-stranded RNA virus, SARS-CoV-2 is highly susceptible to RNA interference (RNAi). Accordingly, small interfering (si)RNAs targeting different regions of SARS-CoV-2 genome can effectively block the expression and replication of the virus. However, the rapid emergence of new SARS-CoV-2 variants with different genomic mutations has led to the problem of viral escape from the targets of RNAi strategy, which has increased the potential of off-target effects by siRNA and decreased the efficacy of long-term use of siRNA treatment. In our study, we enzymatically generated a set of Dicer-substrate (D)siRNA swarms containing DsiRNAs targeting single or multiple conserved sequences of SARS-CoV-2 genome by using in vitro transcription, replication and Dicer digestion system. Pre-transfection of these DsiRNA swarms into Vero E6-TMPRSS2 cells inhibited the replication of several SARS-CoV-2 variants, including the recent Omicron subvariants BQ.1.1 and XBB.1.5. This in vitro investigation of novel DsiRNA swarms provides solid evidence for the feasibility of this new RNAi strategy in the prevention and treatment of SARS-CoV-2 infection., 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 Jiang, Laine, Kolehmainen, Kakkola, Avelin, Väisänen, Poranen, Österlund and Julkunen.)

Background & Aims: Potassium-competitive acid blockers have documented efficacy for erosive esophagitis. We performed a randomized trial in United States subjects diagnosed with non-erosive reflux disease of vonoprazan vs placebo for 4 weeks, followed by a 20-week active-treatment extension., Methods: Adult subjects with heartburn ≥4 days/week during screening without erosive esophagitis on endoscopy were randomized to placebo, vonoprazan 10 mg, or vonoprazan 20 mg. After 4 weeks, subjects on placebo were re-randomized to vonoprazan 10 mg or 20 mg, and those already on vonoprazan continued at the same dose for 20 weeks. Electronic diaries were completed twice daily. The primary endpoint was percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days)., Results: Among 772 randomized subjects, the percentage of 24-hour heartburn-free days was 27.7% for placebo vs 44.8% for vonoprazan 10 mg (least squares mean difference, 17.1%; P < .0001) and 44.4% for vonoprazan 20 mg (least squares mean difference, 16.7%; P < .0001). Differences in percentage of subjects with a 24-hour heartburn-free day for vonoprazan 10 mg vs placebo and vonoprazan 20 mg vs placebo were 8.3% and 11.6% on day 1 and 18.1% and 23.2% on day 2. The mean/median percentages of 24-hour heartburn-free days over the extension period were similar across the 4 study arms: 61%-63%/76%-79%., Conclusions: Vonoprazan reduced heartburn symptoms in subjects diagnosed with non-erosive reflux disease, with the benefit appearing to begin as early as the first day of therapy. Treatment effect persisted after the initial 4-week placebo-controlled period throughout the 20-week extension period. The 2 vonoprazan doses (10 mg and 20 mg) were similar in efficacy. (ClinicalTrials.gov: NCT05195528)., (Published by Elsevier Inc.)

Secondary metabolites often function as antipredator defenses, but when bioactive at low concentrations, their off-target effects on other organisms may be overlooked. Candidate "keystone molecules" are proposed to affect community structure and ecosystem functions, generally originating as defenses of primary producers; the broader effects of animal chemistry remain largely unexplored, however. Here, we characterize five previously unreported polyketides (alderenes A to E) biosynthesized by sea slugs reaching exceptional densities (up to 9000 slugs per square meter) in Northern Hemisphere estuaries. Alderenes comprise only 0.1% of slug wet weight, yet rendered live slugs or dead flesh unpalatable to three co-occurring consumers, making a potential food resource unavailable and redirecting energy flow in critical nursery habitat. Alderenes also displaced infauna from the upper sediment of the mudflat but attracted ovipositing snails. By altering communities, such compounds may have unexpected cascading effects on processes ranging from bioturbation to reproduction of species not obviously connected to the producing organisms, warranting greater attention by ecologists.

Background & Aims: Guidelines recommend use of risk stratification scores for patients presenting with gastrointestinal bleeding (GIB) to identify very-low-risk patients eligible for discharge from emergency departments. Machine learning models may outperform existing scores and can be integrated within the electronic health record (EHR) to provide real-time risk assessment without manual data entry. We present the first EHR-based machine learning model for GIB., Methods: The training cohort comprised 2546 patients and internal validation of 850 patients presenting with overt GIB (ie, hematemesis, melena, and hematochezia) to emergency departments of 2 hospitals from 2014 to 2019. External validation was performed on 926 patients presenting to a different hospital with the same EHR from 2014 to 2019. The primary outcome was a composite of red blood cell transfusion, hemostatic intervention (ie, endoscopic, interventional radiologic, or surgical), and 30-day all-cause mortality. We used structured data fields in the EHR, available within 4 hours of presentation, and compared the performance of machine learning models with current guideline-recommended risk scores, Glasgow-Blatchford Score, and Oakland Score. Primary analysis was area under the receiver operating characteristic curve. Secondary analysis was specificity at 99% sensitivity to assess the proportion of patients correctly identified as very low risk., Results: The machine learning model outperformed the Glasgow-Blatchford Score (area under the receiver operating characteristic curve, 0.92 vs 0.89; P < .001) and Oakland Score (area under the receiver operating characteristic curve, 0.92 vs 0.89; P < .001). At the very-low-risk threshold of 99% sensitivity, the machine learning model identified more very-low-risk patients: 37.9% vs 18.5% for Glasgow-Blatchford Score and 11.7% for Oakland Score (P < .001 for both comparisons)., Conclusions: An EHR-based machine learning model performs better than currently recommended clinical risk scores and identifies more very-low-risk patients eligible for discharge from the emergency department., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Description: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) is to summarize the available evidence and offer expert Best Practice Advice on the integration of potassium-competitive acid blockers (P-CABs) in the clinical management of foregut disorders, specifically including gastroesophageal reflux disease, Helicobacter pylori infection, and peptic ulcer disease., Methods: This expert review was commissioned and approved by the AGA Institute Governing Board and CPU Committee to provide timely guidance on a topic of high clinical importance to the AGA membership. This CPU expert review underwent internal peer review by the CPU Committee and external peer review through the standard procedures of Gastroenterology. These Best Practice Advice statements were developed based on review of the published literature and expert consensus opinion. Because formal systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Based on nonclinical factors (including cost, greater obstacles to obtaining medication, and fewer long-term safety data), clinicians should generally not use P-CABs as initial therapy for acid-related conditions in which clinical superiority has not been shown. BEST PRACTICE ADVICE 2: Based on current costs in the United States, even modest clinical superiority of P-CABs over double-dose proton pump inhibitors (PPIs) may not make P-CABs cost-effective as first-line therapy. BEST PRACTICE ADVICE 3: Clinicians should generally not use P-CABs as first-line therapy for patients with uninvestigated heartburn symptoms or nonerosive reflux disease. Clinicians may use P-CABs in selected patients with documented acid-related reflux who fail therapy with twice-daily PPIs. BEST PRACTICE ADVICE 4: Although there is currently insufficient evidence for clinicians to use P-CABs as first-line on-demand therapy for patients with heartburn symptoms who have previously responded to antisecretory therapy, their rapid onset of acid inhibition raises the possibility of their utility in this population. BEST PRACTICE ADVICE 5: Clinicians should generally not use P-CABs as first-line therapy in patients with milder erosive esophagitis (EE) (Los Angeles classification of erosive esophagitis grade A/B EE). Clinicians may use P-CABs in selected patients with documented acid-related reflux who fail therapy with twice-daily PPIs. BEST PRACTICE ADVICE 6: Clinicians may use P-CABs as a therapeutic option for the healing and maintenance of healing in patients with more severe EE (Los Angeles classification of erosive esophagitis grade C/D EE). However, given the markedly higher costs of the P-CAB presently available in the United States and the lack of randomized comparisons with double-dose PPIs, it is not clear that the benefits in endoscopic outcomes over standard-dose PPIs justify the routine use of P-CABs as first-line therapy. BEST PRACTICE ADVICE 7: Clinicians should use P-CABs in place of PPIs in eradication regimens for most patients with H pylori infection. BEST PRACTICE ADVICE 8: Clinicians should generally not use P-CABs as first-line therapy in the treatment or prophylaxis of peptic ulcer disease. BEST PRACTICE ADVICE 9: Although there is currently insufficient evidence for clinicians to use P-CABs as first-line therapy in patients with bleeding gastroduodenal ulcers and high-risk stigmata, their rapid and potent acid inhibition raises the possibility of their utility in this population., (Published by Elsevier Inc.)

Quantum computing offers new heuristics for combinatorial problems. With small- and intermediate-scale quantum devices becoming available, it is possible to implement and test these heuristics on small-size problems. A candidate for such combinatorial problems is the heterogeneous vehicle routing problem (HVRP): the problem of finding the optimal set of routes, given a heterogeneous fleet of vehicles with varying loading capacities, to deliver goods to a given set of customers. In this work, we investigate the potential use of a quantum computer to find approximate solutions to the HVRP using the quantum approximate optimization algorithm (QAOA). For this purpose we formulate a mapping of the HVRP to an Ising Hamiltonian and simulate the algorithm on problem instances of up to 21 qubits. We show that the number of qubits needed for this mapping scales quadratically with the number of customers. We compare the performance of different classical optimizers in the QAOA for varying problem size of the HVRP, finding a trade-off between optimizer performance and runtime., (© 2024. The Author(s).)

Host-associated microbiota form complex microbial communities that are increasingly associated with host behavior and disease. While these microbes include bacterial, archaeal, viral, and eukaryotic constituents, most studies have focused on bacteria due to their dominance in the human host and available tools for investigation. Accumulating evidence suggests microbial eukaryotes in the microbiome play pivotal roles in host health, but our understandings of these interactions are limited to a few readily identifiable taxa because of technical limitations in unbiased eukaryote exploration. Here, we combined cell sorting, optimized eukaryotic cell lysis, and shotgun sequencing to accelerate metagenomic discovery and analysis of host-associated microbial eukaryotes. Using synthetic communities with a 1% microbial eukaryote representation, the eukaryote-optimized cell lysis and DNA recovery method alone yielded a 38-fold increase in eukaryotic DNA. Automated sorting of eukaryotic cells from stool samples of healthy adults increased the number of microbial eukaryote reads in metagenomic pools by up to 28-fold compared to commercial kits. Read frequencies for identified fungi increased by 10,000× on average compared to the Human Microbiome Project and allowed for the identification of novel taxa, de novo assembly of contigs from previously unknown microbial eukaryotes, and gene prediction from recovered genomic segments. These advances pave the way for the unbiased inclusion of microbial eukaryotes in deciphering determinants of health and disease in the host-associated microbiome.IMPORTANCEMicrobial eukaryotes are common constituents of the human gut where they can contribute to local ecology and host health, but they are often overlooked in microbiome studies. The lack of attention is due to current technical limitations that are heavily biased or poorly recovered DNA from microbial eukaryotes. We developed a method to increase the representation of these eukaryotes in metagenomic sequencing of microbiome samples that allows to improve their detection compared to prior methods and allows for the identification of new species. Application of the technique to gut microbiome samples improved detection of fungi, protists, and helminths. New eukaryotic taxa and their encoded genes could be identified by sequencing a small number of samples. This approach can improve the inclusion of eukaryotes into microbiome research., Competing Interests: M.Z.A. is a board member of the Native BioData Consortium.

Background: The foundation for managing heart failure with reduced ejection fraction (HFrEF) is adherence to guideline-directed medical therapy. Finding an association between medication adherence and patients' health status (their symptoms, function, and quality of life) can be used to underscore its importance to patients., Methods: The association of self-reported medication adherence in US outpatients with HFrEF enrolled in the Change the Management of Patients with Heart Failure registry from 2015 to 2017 was compared with their health status at baseline and 12 months later. A secondary analysis of changes in adherence between baseline and 6 months with 6-month health status was also performed. Medication adherence was assessed with the self-reported 4-item Morisky-Green-Levine Medication Adherence Scale, with scores ≥1 classified as nonadherent. The primary health status outcome was the disease-specific 12-item Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS; range, 0-100; higher is better). Robust linear regression models adjusted for confounders were used., Results: After excluding those who died (n=316) or did not provide 12-month KCCQ (n=1285), 3495 outpatients with HFrEF were included, of whom 1108 (31.7%) reported being nonadherent. Nonadherent participants were younger, had significantly worse baseline health status (-5.83-point difference; P <0.001), and showed less improvement at 12 months (-1.7-point difference in mean change; P =0.017) than adherent participants. Among nonadherent patients at baseline, those whose adherence improved trended toward greater 6-month health status improvements than those remaining nonadherent (fully adjusted difference of 2.52 points; P =0.054)., Conclusions: In HFrEF, medication nonadherence was associated with worse health status and less improvement over the following year. Improvements in adherence were associated with better health status than remaining nonadherent, underscoring the importance of supporting adherence with guideline-directed medical therapy in patients with HFrEF., Competing Interests: Dr El-Zein is currently supported by the National Heart, Lung, and Blood Institute (NHLBI) under award number T32H110837. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institutes of Health. Dr DeVore reports research funding through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent Inc, the NHLBI, Novartis, and Patient-Centered Outcomes Research Institute. He also provides consulting services for Amgen, AstraZeneca, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, Story Health, and Zoll. He has also received nonfinancial support from Abbott for educational activities. Dr Thomas reports research funding Novartis. Dr Albert reports serving as a consultant to Novartis, Amgen, AstraZeneca, and Boston Scientific. Dr Butler has received research support from the National Institutes of Health, PCORI and the European Union; and serves as a consultant for Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Relypsa, StealthPeptide, SC Pharma, Vifor, and ZS Pharma. Dr Hernandez has received research support from the American Heart Association, AstraZeneca, Merck, NHLBI, Luitpold, and Novartis, and honorarium from Bayer, Boston Scientific, and Novartis. Dr Patterson reports research funding from Amgen, Bristol Myers Squibb, Merck, and Novartis, and serves as a consultant to Amgen and Novartis. Dr Spertus reports research funding from NIH, Janssen, and Bristol Meyers Sqiubb. He served as a consultant to Bayer, Bristol Meyers Squibb, Merck, Janssen, Kinksia, Imbria, Cytokinetics, Alnylam, Sanofi Aventis, and United Healthcare. He owns the copyright to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire and Peripheral Artery Questionnaire and serves on the Board of Directors for Blue Cross Blue Shield of Kansas City. Dr Fonarow reports research funding from the National Institutes of Health and consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Merck, Novartis, and Medtronic. The other authors report no conflicts.

The interactions between immune cells and epithelial cells influence the progression of many respiratory diseases, such as chronic obstructive pulmonary disease (COPD). In vitro models allow for the examination of cells in controlled environments. However, these models lack the complex 3D architecture and vast multicellular interactions between the lung resident cells and infiltrating immune cells that can mediate cellular response to insults. In this study, three complementary microphysiological systems are presented to delineate the effects of cigarette smoke and respiratory disease on the lung epithelium. First, the Transwell system allows the co-culture of pulmonary immune and epithelial cells to evaluate cellular and monolayer phenotypic changes in response to cigarette smoke exposure. Next, the human and mouse precision-cut lung slices system provides a physiologically relevant model to study the effects of chronic insults like cigarette smoke with the dissection of specific interaction of immune cell subtypes within the structurally complex tissue environment. Finally, the lung-on-a-chip model provides an adaptable system for live imaging of polarized epithelial tissues that mimic the in vivo environment of the airways. Using a combination of these models, a complementary approach is provided to better address the intricate mechanisms of lung disease., (© 2023 The Authors. Advanced Biology published by Wiley‐VCH GmbH.)

Tenosynovial giant cell tumor (TGCT) is a rare type of neoplasm that may be locally aggressive but is most often benign and can be divided into two subtypes: localized and diffuse. It tends to develop in the joints, bursae, and tendon sheaths primarily in the digits of the hand and less commonly in the forefoot. This soft-tissue mass has many possible differential diagnoses, including lipoma, ganglion cyst, plantar fibroma, and various sarcomas; surgical excision is usually indicated to reach a definitive diagnosis and rule out malignancy. We report a rare case of a 30-year-old woman with atypical plantar hallucal pain and a palpable mass on the plantar lateral aspect of the left hallux. Surgical excision and histopathologic evaluation confirmed a TGCT of the left hallucal flexor tendon sheath. Although it bears clinical resemblance to several other soft-tissue masses, TGCT has numerous pathognomonic features evident with advanced imaging and histologic analysis that help the physician obtain an accurate diagnosis and proceed with appropriate treatment.

Erector spinae plane blocks (ESPB) have shown to provide meaningful chest wall anesthesia and reduce opioid consumption after thoracic surgery. Emergency physicians often use erector spinae plane blocks in the emergency department (ED) for rib fractures when acetaminophen, non-steroidal anti-inflammatory (NSAID), and opioids fail to control pain. They have also demonstrated successful pain management for conditions like herpes zoster, renal colic, burns, and acute pancreatitis for ED patients. With low reported rates of complication and relatively easy landmarks to identify, erector spinae plane blocks are an appealing regional anesthetic technique for emergency physicians to utilize for uncontrolled pain. We present the case of a 58-year-old male presenting to the ED with chest pain from pneumonia which remained unmanageable after acetaminophen, NSAID, and opioid administration. An ultrasound-guided erector spinae plane block was performed in the ED and the patient had a significant reduction in his chest pain., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Description: The purpose of this Clinical Practice Update (CPU) Expert Review is to provide clinicians with guidance on best practices for performing a high-quality upper endoscopic exam., Methods: The best practice advice statements presented herein were developed from a combination of available evidence from published literature, guidelines, and consensus-based expert opinion. No formal rating of the strength or quality of the evidence was carried out, which aligns with standard processes for American Gastroenterological Association (AGA) Institute CPUs. These statements are meant to provide practical, timely advice to clinicians practicing in the United States. This Expert Review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates (CPU) Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Clinical Gastroenterology & Hepatology. BEST PRACTICE ADVICE 1: Endoscopists should ensure that upper endoscopy is being performed for an appropriate indication and that informed consent clearly explaining the risks, benefits, alternatives, sedation plan, and potential diagnostic and therapeutic interventions is obtained. These elements should be documented by the endoscopist before the procedure. BEST PRACTICE ADVICE 2: Endoscopists should ensure that adequate visualization of the upper gastrointestinal mucosa, using mucosal cleansing and insufflation as necessary, is achieved and documented. BEST PRACTICE ADVICE 3: A high-definition white-light endoscopy system should be used for upper endoscopy instead of a standard-definition white-light endoscopy system whenever possible. The endoscope used for the procedure should be documented in the procedure note. BEST PRACTICE ADVICE 4: Image enhancement technologies should be used during the upper endoscopic examination to improve the diagnostic yield for preneoplasia and neoplasia. Suspicious areas should be clearly described, photodocumented, and biopsied separately. BEST PRACTICE ADVICE 5: Endoscopists should spend sufficient time carefully inspecting the foregut mucosa in an anterograde and retroflexed view to improve the detection and characterization of abnormalities. BEST PRACTICE ADVICE 6: Endoscopists should document any abnormalities noted on upper endoscopy using established classifications and standard terminology whenever possible. BEST PRACTICE ADVICE 7: Endoscopists should perform biopsies for the evaluation and management of foregut conditions using standardized biopsy protocols. BEST PRACTICE ADVICE 8: Endoscopists should provide patients with management recommendations based on the specific endoscopic findings (eg, peptic ulcer disease, erosive esophagitis), and this should be documented in the medical record. If recommendations are contingent upon histopathology results (eg, H pylori infection, Barrett's esophagus), then endoscopists should document that appropriate guidance will be provided after results are available. BEST PRACTICE ADVICE 9: Endoscopists should document whether subsequent surveillance endoscopy is indicated and, if so, provide appropriate surveillance intervals. If the determination of surveillance is contingent on histopathology results, then endoscopists should document that surveillance intervals will be suggested after results are available., (Published by Elsevier Inc.)

Background: Acute upper gastrointestinal bleeding (UGIB) is a common emergency requiring hospital-based care. Advances in care across pre-endoscopic, endoscopic and post-endoscopic phases have led to improvements in clinical outcomes., Aims: To provide a detailed, evidence-based update on major aspects of care across pre-endoscopic, endoscopic and post-endoscopic phases., Methods: We performed a structured bibliographic database search for each topic. If a recent high-quality meta-analysis was not available, we performed a meta-analysis with random effects methods and odds ratios with 95% confidence intervals., Results: Pre-endoscopic management of UGIB includes risk stratification, a restrictive red blood cell transfusion policy unless the patient has cardiovascular disease, and pharmacologic therapy with erythromycin and a proton pump inhibitor. Patients with cirrhosis should be treated with prophylactic antibiotics and vasoactive medications. Tranexamic acid should not be used. Endoscopic management of UGIB depends on the aetiology. For peptic ulcer disease (PUD) with high-risk stigmata, endoscopic therapy, including over-the-scope clips (OTSCs) and TC-325 powder spray, should be performed. For variceal bleeding, treatment should be customised by severity and anatomic location. Post-endoscopic management includes early enteral feeding for all UGIB patients. For high-risk PUD, PPI should be continued for 72 h, and rebleeding should initially be evaluated with a repeat endoscopy. For variceal bleeding, high-risk patients or those with further bleeding, a transjugular intrahepatic portosystemic shunt can be considered., Conclusions: Management of acute UGIB should include treatment plans for pre-endoscopic, endoscopic and post-endoscopic phases of care, and customise treatment decisions based on aetiology and severity of bleeding., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: Plasma levels of renalase decrease in acute experimental pancreatitis. We aimed to determine if decreases in plasma renalase levels after ERCP predict the occurrence of post-ERCP pancreatitis (PEP)., Methods: In this prospective cohort study conducted at a tertiary hospital, plasma renalase was determined before ERCP (baseline) and at 30 and 60 minutes after ERCP. Native renalase levels, acidified renalase, and native-to-acidified renalase proportions were analyzed over time using a longitudinal regression model., Results: Among 273 patients, 31 developed PEP. Only 1 PEP patient had a baseline native renalase >6.0 μg/mL, whereas 38 of 242 without PEP had a native renalase > 6.0 μg/mL, indicating a sensitivity of 97% (30/31) and specificity of 16% (38/242) in predicting PEP. Longitudinal models did not show differences over time between groups., Conclusions: Baseline native renalase levels are very sensitive for predicting PEP. Further studies are needed to determine the potential clinical role of renalase in predicting and preventing PEP., Competing Interests: Disclosure The following author disclosed financial relationships: G. Desir: Inventor on several issued patents related to renalase discovery and therapeutic use; equity position in Bessor and its subsidiary, Personal Therapeutics (renalase is licensed to Bessor Pharma). All other authors disclosed no financial relationships. Thiruvengadam Muniraj received grant support for this study. Research support for this study was provided by a grant from the AGA-Medtronic Research and Development Pilot Award in Technology 2019., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objective: To determine how a large scale, multicomponent, pharmacy based intervention to reduce proton pump inhibitor (PPI) overuse affected prescribing patterns, healthcare utilization, and clinical outcomes., Design: Difference-in-difference study., Setting: US Veterans Affairs Healthcare System, in which one regional network implemented the overuse intervention and all 17 others served as controls., Participants: All individuals receiving primary care from 2009 to 2019., Intervention: Limits on PPI refills for patients without a documented indication for long term use, voiding of PPI prescriptions not recently filled, facilitated electronic prescribing of H2 receptor antagonists, and education for patients and clinicians., Main Outcome Measures: The primary outcome was the percentage of patients who filled a PPI prescription per 6 months. Secondary outcomes included percentage of days PPI gastroprotection was prescribed in patients at high risk for upper gastrointestinal bleeding, percentage of patients who filled either a PPI or H2 receptor antagonist prescription, hospital admission for acid peptic disease in older adults appropriate for PPI gastroprotection, primary care visits for an upper gastrointestinal diagnosis, upper endoscopies, and PPI associated clinical conditions., Results: The number of patients analyzed per interval ranged from 192 607 to 250 349 in intervention sites and from 3 775 953 to 4 360 868 in control sites, with 26% of patients receiving PPIs before the intervention. The intervention was associated with an absolute reduction of 7.3% (95% confidence interval -7.6% to -7.0%) in patients who filled PPI prescriptions, an absolute reduction of 11.3% (-12.0% to -10.5%) in PPI use among patients appropriate for gastroprotection, and an absolute reduction of 5.72% (-6.08% to -5.36%) in patients who filled a PPI or H2 receptor antagonist prescription. No increases were seen in primary care visits for upper gastrointestinal diagnoses, upper endoscopies, or hospital admissions for acid peptic disease in older patients appropriate for gastroprotection. No clinically significant changes were seen in any PPI associated clinical conditions., Conclusions: The multicomponent intervention was associated with reduced PPI use overall but also in patients appropriate for gastroprotection, with minimal evidence of either clinical benefits or harms., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organization for the submitted work; JEK has received speaking fees from Anticoagulation Forum; LL has received consulting fees from Phathom Pharmaceuticals; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Prime editing enables the precise modification of genomes through reverse transcription of template sequences appended to the 3' ends of CRISPR-Cas guide RNAs 1 . To identify cellular determinants of prime editing, we developed scalable prime editing reporters and performed genome-scale CRISPR-interference screens. From these screens, a single factor emerged as the strongest mediator of prime editing: the small RNA-binding exonuclease protection factor La. Further investigation revealed that La promotes prime editing across approaches (PE2, PE3, PE4 and PE5), edit types (substitutions, insertions and deletions), endogenous loci and cell types but has no consistent effect on genome-editing approaches that rely on standard, unextended guide RNAs. Previous work has shown that La binds polyuridine tracts at the 3' ends of RNA polymerase III transcripts 2 . We found that La functionally interacts with the 3' ends of polyuridylated prime editing guide RNAs (pegRNAs). Guided by these results, we developed a prime editor protein (PE7) fused to the RNA-binding, N-terminal domain of La. This editor improved prime editing with expressed pegRNAs and engineered pegRNAs (epegRNAs), as well as with synthetic pegRNAs optimized for La binding. Together, our results provide key insights into how prime editing components interact with the cellular environment and suggest general strategies for stabilizing exogenous small RNAs therein., (© 2024. The Author(s).)

Background: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment., Methods: We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539)., Findings: Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5-31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13-30]). The mean change in MG-QOL15r was -10·4 (95% CI -18·9 to -1·3) with mycophenolate mofetil and -6·8 (-17·2 to 3·6) with azathioprine (mean difference -3·3, 95% CI -7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI -0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI -4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths., Interpretation: More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis., Funding: Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America., Competing Interests: Declaration of interests PN has received payments to her institution from the Patient-Centered Outcomes Research Institute (PCORI); travel support from the Myasthenia Gravis Foundation of America; research support from Alexion, Momenta/Janssen, and UCB/Ra; honoraria from the American Academy of Neurology and the American Association of Neuromuscular and Electrodiagnostic Medicine; payment for continuing medical education presentations from WebMD, AcademicCME, Neurodiem, Partners for Advancing Clinical Education, PeerVoice, and Haymarket CME; has participated in advisory boards for Alexion, Argenx, Janssen, and Dianthus; has served on a data safety monitoring board for Sanofi; and received consulting fees from GlaxoSmithKline and CVS Pharmacy. DBS has received payments to his institution from PCORI, consulting fees from Partnership for Health Analytic Research (PHAR), Becker, Modus Outcomes, Wise, Windrose Consulting Group, Avora Capital Advisors, and Sentient; publishing royalties for the book Single Fiber EMG; has participated in a data safety monitoring board for Horizon, Roche, Janssen, and Sanofi-Aventis; holds stocks in Regeneron and has participated in medical advisory boards for Accordant Health Services. JTG has received payments to their institution from PCORI and is currently employed by Argenx. LT, DT, JB, RD, AK, KB, and BL declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: We estimate the economic impact of applying risk assessment tools to identify very low-risk patients with upper gastrointestinal bleeding who can be safely discharged from the emergency department using a cost minimization analysis., Methods: We compare triage strategies (Glasgow-Blatchford score = 0/0-1 or validated machine learning model) with usual care using a Markov chain model from a US health care payer perspective., Results: Over 5 years, the Glasgow-Blatchford score triage strategy produced national cumulative savings over usual care of more than $2.7 billion and the machine learning strategy of more than $3.4 billion., Discussion: Implementing risk assessment models for upper gastrointestinal bleeding reduces costs, thereby increasing value., (Copyright © 2023 by The American College of Gastroenterology.)

CRISPR-enabled screening is a powerful tool for the discovery of genes that control T cell function and has nominated candidate targets for immunotherapies 1-6 . However, new approaches are required to probe specific nucleotide sequences within key genes. Systematic mutagenesis in primary human T cells could reveal alleles that tune specific phenotypes. DNA base editors are powerful tools for introducing targeted mutations with high efficiency 7,8 . Here we develop a large-scale base-editing mutagenesis platform with the goal of pinpointing nucleotides that encode amino acid residues that tune primary human T cell activation responses. We generated a library of around 117,000 single guide RNA molecules targeting base editors to protein-coding sites across 385 genes implicated in T cell function and systematically identified protein domains and specific amino acid residues that regulate T cell activation and cytokine production. We found a broad spectrum of alleles with variants encoding critical residues in proteins including PIK3CD, VAV1, LCP2, PLCG1 and DGKZ, including both gain-of-function and loss-of-function mutations. We validated the functional effects of many alleles and further demonstrated that base-editing hits could positively and negatively tune T cell cytotoxic function. Finally, higher-resolution screening using a base editor with relaxed protospacer-adjacent motif requirements 9 (NG versus NGG) revealed specific structural domains and protein-protein interaction sites that can be targeted to tune T cell functions. Base-editing screens in primary immune cells thus provide biochemical insights with the potential to accelerate immunotherapy design., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)